Hemodynamics and Vascular Regulation

Local Shear Stress and Brachial Artery Functions in End-Stage Renal Disease

Francis H. Verbeke, Mohsen Agharazii, Pierre Boutouyrie, Bruno Pannier, Alain P. Guérin and Gérard M. London
JASN February 2007, 18 (2) 621-628; DOI: https://doi.org/10.1681/ASN.2006040400

Abstract

Physiologic laminar shear stress (SS) is crucial for normal vascular structure and function. As a result of anemia-related lower whole-blood viscosity (WBV), SS could be reduced in patients with ESRD and might be associated with arterial functional alterations. In 44 patients with ESRD and 25 control subjects, brachial artery (BA) compliance and BA diameter changes (flow-mediated dilation [FMD[) were evaluated in response to local shear rate and SS changes during hand warming–induced hyperemia. Patients with ESRD and control subjects had similar BA blood flow, but SS was lower in patients with ESRD (P < 0.001), with lower shear rate (P < 0.01) and lower WBV (P < 0.0001). In control subjects, SS was positively (and physiologically) correlated with arterial diameter (P < 0.001). In contrast, in patients with ESRD, larger arterial diameter was associated with low SS (P < 0.05) and increased arterial wall elastic modulus (P < 0.001). Anemia-associated low WBV aggravates low shear rate, further contributing to SS reduction. These abnormalities were associated with decreased vasodilating response to endothelial mechanical stimulation. Compared with control subjects, BA compliance and FMD increases in response to hand warming–induced increased SS were lower in ESRD patients (P < 0.01), whereas their BA diameter response to glyceryl trinitrate did not differ. The long-term WBV and SS increases after anemia correction improved FMD (P < 0.01) and BA compliance (P < 0.05) and heightened arterial wall sensitivity to mechanical stimulation. Maintenance low SS as a result of anemia could play an indirect role in arterial dysfunction in patients with ESRD.

Physiologic laminar fluid shear stress (SS) is responsible for endothelial cell survival and quiescence and their secretion of substances that favor anticoagulation, inhibit inflammation, induce vasodilation, and exert atheroprotective effects in vivo (1–3). SS maintenance is crucial for normal vascular structure and function (1–5). High SS induces acute changes of the conduit artery function (flow-mediated dilation [FMD]) (4) and arterial remodeling with modified arterial wall properties (5). Outward remodeling, arterial stiffening, and decreased FMD are observed in patients with ESRD (6–9). FMD, as assessed by brachial artery (BA) diameter changes (10), enables examination of the arterial response to local flow independent of the maneuver that is used to induce flow changes (11). BA diameter changes usually are referred to as blood flow changes. However, it was shown that, under conditions of similar blood flow changes, FMD depended on SS changes that were induced by whole-blood viscosity (WBV) modifications (12). Arterial SS is lower in ESRD (13), and we hypothesized that lower FMD in the context of ESRD could reflect diminished SS and not only endothelial alterations. SS is a major factor implicated in vascular remodeling (1,5) and, as such, could influence the mechanical properties of arteries (5). Although arterial remodeling and stiffening are present in patients with ESRD (6), the relationships between these alterations and SS remain to be investigated in uremic patients.

In the case of laminar flow, the SS (τ) usually is estimated using the Hagen-Poiseuille formula τ = 4 μQ/πr (3), where Q is blood flow, r is vessel radius, and μ is viscosity, and not directly measured. The inclusion of arterial radius in the equations that are used to determine FMD and SS could generate an erroneous mathematical relationship between these variables that does not necessarily reflect a physiologic reality. Newly developed technologies enable direct in vivo ultrasound measurements of arterial wall shear rate and its distribution and SS determination (5,13,14). To define the interrelationships between local SS and BA wall properties, including capacitive (BA compliance [BAC]), and conduit functions (FMD), we measured in vivo shear rate, SS, BA diameter, and BAC changes in response to progressive hand warming in patients with ESRD and healthy control subjects.

Materials and Methods

Forty-four patients who had ESRD ans were on hemodialysis for at least 3 mo (median 45; range 3 to 364 mo) were included. ESRD resulted from chronic glomerulonephritis (n = 18), interstitial nephritis (n = 6), polycystic kidney disease (n = 6), hypertensive nephroangiosclerosis (n = 8), and other (n = 6). Patients were eligible for inclusion when they had no clinical cardiovascular complication and they agreed to participate in the study, which was approved by our institutional review board. Patients underwent dialysis for 4 to 6 h three times weekly to control body fluids and blood chemistries. Twenty-five gender-, age-, and body surface area–matched healthy control subjects were evaluated for comparison. Thirteen patients with ESRD received antihypertensive therapy (angiotensin-converting enzyme inhibitor and/or calcium channel blocker), which was stopped 10 d before the study. Six patients took atorvastatin (20 mg/d). Erythropoietin was administered to 39 patients. For the 10 patients whose hemoglobin levels were below the target of 110 g/L, the entire procedure was repeated after that target had been reached, with combined erythropoietin and intravenous iron adjustment, and remained stable for 3 mo.

BA Hemodynamic Measurements

Measurements were obtained in a temperature-controlled (23 ± 1°C) room before the first hemodialysis of the week. BP was measured with a mercury sphygmomanometer after 15 min of recumbency using phases I and V of the Korotkoff sounds, respectively, as the systolic and diastolic BP.

BA internal diameter, stroke changes in BA diameter, BA intima-media thickness, and shear rate were measured independently with a high-resolution B-mode (7.5-MHz transducer) echo-tracking system (Wall-Track System; PIE Medical, Maastricht, The Netherlands) as previously described (6,15). Briefly, vessel walls are identified automatically, and their displacement is tracked throughout the cardiac cycle. According to phase and amplitude, the radiofrequency signal during six cardiac cycles is digitized and stored until analysis. The accuracy of the system is ±30 μm for diastolic diameter (Dd) and less than ±1 μm for stroke-diameter change. Radiofrequency matrixes were acquired during 2 to 4 s, and acquisitions were repeated every 10 s. One patient period corresponded to 450 radiofrequency acquisitions (500 to 700 megabytes). The entire procedure was videotaped on S-VHS tapes for image analysis. BAC and BA distensibility were determined from changes of pulse pressure (ΔP) and from systolic − diastolic (Ds − Dd; stroke changes in diameter) changes in BA diameter (D) as BAC = [πDd(Ds − Dd)/2]/ΔP(m2× kPa−1× 10−7); and BA distensibility = 2[(Ds − Dd)/Dd]/ΔP(kPa−1× 10−3) (6). BA incremental elastic modulus (Einc) was determined according to the previously reported formula (6): Einc = [(BA lumen cross-sectional area/BA wall cross-sectional area + 1) × 3]/BA distensibility. Circumferential BA wall stress (σ) was calculated using the Lamé equation: σ = (BP × Dd)/2 intima-media thickness).

Shear rate was measured with the same device but with different settings, as previously reported (5,13,14,16). The echo system is shifted to pulsed Doppler mode, and a 30° oblique radiofrequency line is digitized at high frequency (24 MHz). The Doppler shift is determined in two successive wavelength windows; blood velocities are measured in co-adjacent windows until the wall is reached, taking into account systolic distension. Vessel-wall motion is filtered out by an autoadaptive high-pass filter set at 20 Hz for BA measurement (low velocities and small distension). Therefore, blood velocities in the range of 10 mm/s to 2 m/s could be measured, and flow velocity profiles across the lumen and during the cardiac cycle could be constructed. Wall shear rate then was calculated by spatial derivation of blood velocities along the diameter, as a function of depth and time; the lower threshold was 7/s. Mean shear rate was the average of six heart beats for each hand-warming step. SS then was calculated using WBV measured at shear rate of 60 to 241/s. WBV was measured using a cone-plate viscometer (EX100 CTB; Brookfield, Middleboro, MA) at 37°C.

Hand-Warming Protocol

Twenty-two control subjects and 39 patients with ESRD agreed to participate in this protocol. The glove-protected hand of the arm opposite the arteriovenous shunt was introduced into a water-filled, thermocontrolled device (Polystat 1; Bioblock Scientific, Illkirch, France) (11,16,17). The arm was positioned and immobilized in an inflatable splint. The echo-tracking probe was placed over the BA, 1 to 2 cm above the elbow, and positioned carefully with a stereotactic arm parallel to the main BA axis. Image quality was maintained throughout the study by gentle adjustments in the x, y, and z axes. The skin was gel-coated to avoid any direct contact with the probe. After 15 min of rest, the measurements were made at a water temperature of 35°C (neutrality). The water temperature then was increased in 5 min increments from 35°C to 38°C, 41°C and 44°C. BA hemodynamic measurements were repeated five times during each step and averaged. Maximum FMD was expressed as the BA diameter increase at 44°C in absolute values in μm. Each subject’s SS and BA diameter relationship was evaluated and expressed in absolute values as FMD (μm)/ΔSS (dynes/cm2). After a 20-min recovery period, BA diameter was measured before and after sublingual administration of 150 μg of glyceryl trinitrate (GTN).

Blood chemistries were determined before hemodynamic study and included blood urea, serum albumin, serum high-sensitivity C-reactive protein, blood lipids, parathormone, homocysteine, and Kt/V. The hemodynamic procedure was repeated in 10 patients after target hemoglobin of ≥110 g/L had been reached and stabilized for 3 mo. For these patients, all measurements were obtained by the same observer, who was blinded to their status.

Statistical Analyses

Data are expressed as means ± SEM or as medians according to the distribution. Baseline between-group comparisons for quantitative variables were performed using the Mann-Whitney U test when the control subjects and patients with ESRD were compared. χ2 test was used for categorical variables. Baseline values before and at hemoglobin target for the group with anemia improvement were compared using Wilcoxon’s signed-rank test. ANOVA for repeated measures was used to evaluate the effects of hand warming on BA diameter, blood velocity, SR, SS, BAC, and BA distensibility. Pearson and Spearman correlation coefficients were used to assess the relationship between clinical and arterial parameters. P < 0.05 after Bonferroni correction for the number of correlations studied was considered significant. For the multiple regression analysis, the subset of retained independent variables was analyzed. Analyses were performed using NCSS 2000 (G. Hintze, Kaysville, UT).

Results

Characteristics of the Study Populations

BA geometry and vessel wall properties are summarized in Table 1. The BA inner diameter was larger in patients with ESRD (P < 0.01) with thicker walls and similar wall thickness/inner diameter ratios. Their BA incremental elastic modulus also was higher with lower BAC and BA distensibility (P < 0.001). Compared with control subjects, the patients with ESRD had similar mean BA blood flow, with lower mean flow velocity (P < 0.01), lower mean shear rate (P < 0.01), and lower mean SS (P < 0.001). The BA circumferential wall stress was comparable in the two groups. The BA inner diameter was positively correlated with age in control subjects, with an upward shift for patients with ESRD (Figure 1).The BA elastic modulus increased with age in patients with ESRD (P < 0.01), whereas the association that was observed in control subjects was weak (P < 0.05; Figure 1). In control subjects, the baseline BA mean SS was not correlated with age, whereas a negative correlation (P = 0.05) was observed in patients with ESRD. As shown in Figure 2, control subjects had a positive (and expected) correlation between baseline mean SS and BA diameter (P < 0.001) and between BA diameter and BAC (P < 0.01). In contrast, a negative correlation between baseline SS and baseline BA diameter was observed in patients with ESRD (P < 0.05; Figure 2), and the correlation between BAC and diameter was NS. Both groups showed a significant positive correlation between SS and BAC, and in patients with ESRD, this correlation was BA diameter independent. Peak shear rate and peak SS were significantly lower in patients with ESRD, and they were not correlated with arterial parameters.

Figure 1.
Figure 1.

Correlations for control subjects (▴) and patients with ESRD (•) between age and brachial artery (BA) baseline diameter, BA elastic modulus, and BA shear stress (SS).

Figure 2.
Figure 2.

Correlations in patients with ESRD (•) and control subjects (▴) between baseline BA SS and baseline BA diameter, between baseline BA diameter and BA compliance (BAC), and baseline BA SS and BAC.

View this table:
Table 1.

Clinical data and BA characteristicsa

Effect of Hand Warming on BA Hemodynamics

BA responses to hand warming are shown in Figure 3 and Table 2. Hand warming induced significant flow velocity, shear rate, and SS increases in both groups (group effects P = 0.870; interaction P = 0.40). Hand warming induced progressive BA diameter and BAC rises with striking differences between patients with ESRD and control subjects. A significant upward shift of the BA diameter–SS relationship and downward shift of BAC–SS relationships were observed in patients with ESRD, with control values generating steeper slopes of these relationships (group effect P < 0.01; interaction P < 0.001). FMD/ΔSS and ΔBAC/ΔSS were significantly lower for patients with ESRD. FMD and FMD/ΔSS in patients with ESRD was not correlated with any of the blood chemistry parameters, age, or systolic BP (r = −0.265; P = 0.118). Both groups responded similarly to GTN, but the FMD/GTN ratio was lower in patients with ESRD (P < 0.01).

Figure 3.
Figure 3.

Relationships for patients with ESRD and control subjects between BA diameter and BAC and BA SS changes during hand warming.

View this table:
Table 2.

BA response to hand warming (44°C, baseline)a

Effects of Long-Term SS Increase on BA Hemodynamics

Effects of anemia attenuation on BA function are shown in Table 3 and Figure 4. In seven patients, anemia correction was achieved with increased erythropoietin dosage (80 ± 31 versus 53 ± 24 U/kg per wk; P < 0.05), but in three patients, the erythropoietin dosage was unchanged and anemia improvement was achieved with iron-deficiency correction. Achievement of the target hemoglobin levels had no effect on baseline BA diameter and flow velocity and baseline shear rate. However, baseline SS was significantly higher as a result of increased WBV. Arterial stiffness declined with significant increases of baseline BAC and BA distensibility (P < 0.01) and decreased elastic modulus (P < 0.01). FMD (P < 0.01), FMD/ΔSS (P < 0.01), and ΔBAC/ΔSS (P < 0.05) increased significantly, but the BA diameter response to GTN was not significantly different. Blood chemistries did not change (data not shown).

Figure 4.
Figure 4.

Effects of anemia correction on flow-mediated dilation (FMD), FMD/ΔSS, baseline BAC, and response of BAC to hand warming.

View this table:
Table 3.

Effects of long-term anemia correction on baseline BA characteristics and responses to hand warming (44°C, baseline)a

Discussion

This study is the first to analyze the relationship between in vivo measured shear rate and SS and structural and functional properties of a peripheral conduit artery in patients with ESRD. Patients with ESRD were characterized by outward remodeling of BA, with larger inner diameter and increased stiffness. The outward remodeling was not associated with higher blood flow but with an acceleration of age-associated changes. Whereas BA circumferential wall stress did not differ from that in control subjects, SS was reduced significantly in patients with ESRD as a result of lower shear rate and decreased WBV. Hand warming–induced SS augmentation was associated with FMD and enhanced BAC, which were significantly less pronounced in patients with ESRD, but dilation in response to GTN did not differ in control subjects and patients with ESRD. In patients with ESRD, the partial anemia correction increased SS as a result of enhanced WBV and was associated with an increased FMD and improved BAC.

Arterial dilation and increased arterial stiffness are well documented in patients with ESRD (6) and were observed previously also in patients with mild to moderate chronic kidney disease (18). Outward remodeling with increased inner diameter is a vessel wall adaptation to chronic blood flow change and is regulated by SS-induced changes of the endothelium. These changes typically are observed in the BA at the arteriovenous fistula site (5). Acutely, fistula creation increases blood flow, mean SS (but not peak SS), and BA diameter. With time, blood flow remains high and the diameter increases further, but this modification did not result in SS restoration (5). A positive (physiologic) correlation between local SS and BA diameter was seen in control subjects (Figure 2) but not in patients with ESRD. The BA remodeling that we observed in patients with ESRD was not associated with higher blood flow, and SS was low, not high, suggesting an origin other than chronic flow overload.

Arterial changes that occur during chronic kidney disease and ESRD are more consistent with acceleration of age-related arterial remodeling (i.e., arteriosclerosis), characterized by increased arterial inner dimensions and wall stiffening (19). Arterial dilation and increased wall thickness during aging are known phenomena in the general population (20) and also were seen in our study groups (Figure 1). Whereas circumferential wall stress did not differ in patients with ESRD and control subjects, SS was low in patients, resulting from lower shear rate and low WBV. Shear rate is inversely proportional to the third power of arterial radius, and, in the presence of arterial enlargement with normal blood flow, the lower shear rate (and SS) in patients with ESRD could reflect age-associated advanced arteriosclerosis. In agreement with Dammers et al. (21), BA SS was independent of age in control subjects but declined with age in patients with ESRD (Figure 1). Aging also is associated with arterial wall stiffening, which also is accelerated in patients with ESRD, with an upward shift and steeper age-related rise of the BA elastic modulus (Figure 1) and reduced BAC and BA distensibility. Under physiologic conditions, BAC increases with the inner diameter of an artery, as was observed in our control subjects (Figure 2) but not our patients with ESRD, in whom the “diameter effect” was outweighed by the increased elastic modulus (reflecting stiffness of the vessel wall biomaterials). Figure 2 also shows the correlations between SS and BAC. In control subjects, this correlation could result from SS-induced enlargement of the BA diameter and from the physiologic diameter–compliance correlation. In patients with ESRD, the correlation between SS and BAC was independent of baseline diameter and the SS–diameter relationship (Figure 2), suggesting that SS influences directly arterial compliance, as also indicated by the effects of hand warming–induced SS changes on BAC (Figure 3).

Several studies reported that FMD as evaluated by reactive hyperemia is lower in patients with ESRD (6–9). FMD is expressed most frequently as a percentage change of baseline arterial diameter (FMD%) (10). However, expressing FMD as a percentage of an initially dilated artery, as found in ESRD, could minimize erroneously the vasodilation response. For this reason, in this study, we expressed BA diameter changes in absolute values (FMDμm). A study that was conducted with nonuremic individuals showed that, under conditions of similar blood flow changes, short-term reactive hyperemia was influenced by WBV modifications (12). Therefore, in the presence of conditions that are characterized by lower WBV, FMD could not be assessed and compared accurately by quantification of the stimulus only through blood flow changes and rather should be based on local SS changes (12). The relationship between SS and corresponding BA diameter changes was different in patients with ESRD and control subjects. It is characterized by a significant upward shift of the SS–BA diameter relationship in patients with ESRD and a much steeper (P < 0.001) slope in control subjects (Figure 3). The significantly milder slopes of BA diameter and BAC–SS correlations favors less BA sensitivity to mechanical stimulation. BA response to GTN did not differ significantly between the two groups, but the FMD/GTN ratio was lower in patients with ESRD, indicating a disturbed endothelial response to SS (7).

The hematocrit is a major determinant of WBV, and a modest hematocrit decrease has been shown to impair FMD acutely in healthy humans (12). We tried to analyze the possibility that long-term SS increase might improve FMD by repeating the study after anemia correction. Whereas BA diameter, blood velocity, and shear rate did not change significantly, SS rose. This rise was due to higher WBV. Higher SS was associated with improved FMD and BAC (Table 3; Figure 4). Improved FMD could result from higher mechanical stimulation (FMD/ΔSS would remain unchanged) or from enhanced arterial wall “sensitivity” to SS (FMD/ΔSS would increase). The observed increases of FMD/ΔSS pleads for enhanced arterial wall sensitivity to SS. Factors that are known to contribute to endothelial dysfunction in ESRD include reduced bioactivity of the nitric oxide (NO) pathway with decreased endothelial NO synthase (eNOS) activity or inhibition via accumulation of endogenous inhibitors, such as asymmetric dimethyl-arginine (22,23). That the dialysis technique and blood chemistries were unchanged during anemia treatment does not support a possible role for a change in the uremic milieu, and alternative explanations should be considered, such as a direct impact of increased SS or an effect of anemia treatment with erythropoietin. SS is a potent in vivo regulator of vascular endothelium integrity, and physiologic levels of laminar SS suppress endothelial cell apoptosis by regulating eNOS and inducing expression of apoptosis inhibitors (1–3,24). Another possibility is that FMD improvement could be attributed to higher erythropoietin dosages and a direct action of erythropoietin. In vitro studies on cultured endothelial cells provided evidence that erythropoietin can act directly on the endothelium by upregulating eNOS, thereby increasing NO availability (25). It has been shown that long-acting erythropoietin analogue enhanced endothelial progenitor cell proliferation and differentiation, thereby conferring vessel and tissue protection (26,27). Experimental studies in rodents demonstrated that erythropoietin administration was associated with elevated eNOS activity and increased NO production in vivo (28). The direct effect of a higher erythropoietin dosage cannot be excluded in some patients, but, at baseline, FMD and erythropoietin dosage were not correlated, and, in three patients, anemia correction was achieved with iron therapy and not erythropoietin. Conversely, several studies in normal control subjects and hemodialysis patients showed that acute intravenous injection of erythropoietin impaired endothelium-dependent vasorelaxation (29), enhanced vasoconstrictor tone (30), and raised the serum concentration of endothelin-1 (31).The principal limitation of our study is the small number of patients investigated after anemia correction, which limited the statistical power and the possibility of more detailed analyses of mechanisms relating arterial functional changes to hemodynamic stresses and eventual effects of erythropoietin.

Conclusion

Physiologic laminar fluid SS promotes endothelial cell survival, and its maintenance is antiatherogenic and crucial for normal vascular structure and function. Our results indicate that BA SS is low in patients with ESRD, as a consequence of lower shear rate and lower WBV. In the presence of normal blood flow, the lower shear rate in ESRD is associated with accelerated aging of the artery, characterized by enlarged arterial inner diameter and wall stiffening. Anemia and low WBV enhance the role of low shear rate, further contributing to SS lowering and creation of a vicious cycle. By maintaining low SS, anemia could play an indirect role in arterial dysfunctions in patients with ESRD. These abnormalities are associated with a diminished vasodilating response to endothelial mechanical stimulation. The long-term WBV and SS increases with anemia correction led to improved FMD and BAC and enhanced arterial wall sensitivity to mechanical stimulation. The exact mechanisms that contribute to these improvements remain to be analyzed further.

Disclosures

None.

Acknowledgments

This work was funded by unrestricted grants from Ortho-Biotech Biopharmaceuticals EMEA, CKD Steering Committee Project No. 124026, and Groupe dÉtude de la Physiopathologie de l’Insuffisance Rénale.

We express special thanks to Dr. Dieter Frei for support.

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

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Local Shear Stress and Brachial Artery Functions in End-Stage Renal Disease
Francis H. Verbeke, Mohsen Agharazii, Pierre Boutouyrie, Bruno Pannier, Alain P. Guérin, Gérard M. London
JASN Feb 2007, 18 (2) 621-628; DOI: 10.1681/ASN.2006040400
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